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Aims Mutations in the lamin A/C gene (LMNA) cause a variety of clinical phenotypes, including dilated cardiomyopathy. LMNA is one of the most prevalent mutated genes in dilated cardiomyopathy, and is associated with a high risk of arrhythmias, sudden cardiac death, and heart failure. There are few data on the impact of age and gender on cardiac disease penetrance and mortality. Methods and results In a multicentre cohort of 269 LMNA mutation carriers, we evaluated gender-specific penetrance of cardiac involvement and major cardiac events. All-cause mortality of mutation carriers [standardized mortality ratio (SMR)] was determined. Cardiac disease penetrance was age dependent and almost complete at the age of 70 years. The presence of an LVEF ≤45% was significantly higher in men (P < 0.001). However, there was no difference between genders in the prevalence of atrioventricular block, atrial tachyarrhythmias, and non-sustained ventricular tachycardia. Malignant ventricular arrhythmias (26% vs. 8%) and end-stage heart failure (28% vs. 14%) were more common in men than in women (P < 0.001 and P = 0.006, respectively). All-cause mortality of mutation carriers was significantly increased [SMR 4.0, 95% confidence interval (CI) 2.8–5.2] between the ages of 15 and 75 years. Mortality in men was higher than in women (hazard ratio 2.2, 95% CI 1.2–4.3). Conclusions This large cohort of LMNA mutation carriers demonstrates a high cardiac disease penetrance and a high mortality in mutation carriers. Male mutation carriers have a worse prognosis due to a higher prevalence of malignant ventricular arrhythmias and end-stage heart failure. [ABSTRACT FROM PUBLISHER]

Abstract: Background: Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study. Aims: To describe a cardiological phenotype characterized by RCM plus AVB due to desmin accumulation caused by DES defects. Methods and results: Desmin accumulation was diagnosed by means of ultrastructural and immunocytochemical studies of EMB in four unrelated probands with RCM and AVB. Candidate genes [DES and αB-crystallin (CRYAB)] were screened using sequence analysis. Four DES gene mutations were identified: three new (R16C, T453I and a 10 bp deletion at the exon–intron boundary of exon 3 disrupting the donor splice site) and one known (R406W). The disease was autosomal dominant in two families, recessive in one and associated with a de novo mutation in one. The mutations cosegregated with phenotype in all patients. CRYAB gene screening was negative. Conclusions: A cardiac phenotype characterized by RCM and AVB caused by desmin accumulation is associated with DES mutations. Although the mutations affected different domains, the cardiac phenotype was identical. [Copyright &y& Elsevier]